{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:47:19Z","timestamp":1785422839542,"version":"3.56.0"},"posted":{"date-parts":[[2025,7,20]]},"group-title":"Neuroscience","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T00:00:00Z","timestamp":1752969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["AG66986"],"award-info":[{"award-number":["AG66986"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AG79569"],"award-info":[{"award-number":["AG79569"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AG072973"],"award-info":[{"award-number":["AG072973"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The membrane-embedded \u03b3-secretase complex is involved in the intramembrane cleavage of \u223c 150 substrates. Cleavage of amyloid precursor protein (APP)-derived substrate C99 generates 38-43-residue secreted amyloid \u03b2-peptides (A\u03b2), with the aggregation-prone 42-residue form (A\u03b242) particularly implicated in the pathogenesis of Alzheimer\u2019s Disease (AD). However, whether A\u03b242 is the primary driver of neurodegeneration in AD remains unclear. Dominant mutations in APP or presenilin\u2014the catalytic component of \u03b3-secretase\u2014cause early-onset familial AD (FAD) and reduce one or more steps in the multi-step processive proteolysis of C99 to A\u03b2 peptides, apparently through stabilization of \u03b3-secretase enzyme-substrate (E-S) complexes. To investigate mechanisms of neurodegeneration in FAD, we developed new\n                  <jats:italic>C. elegans<\/jats:italic>\n                  models co-expressing wild-type or FAD-mutant C99 substrate and presenilin-1 (PSEN1) variants in neurons, allowing intramembrane processing of C99 to A\u03b2\n                  <jats:italic>in vivo.<\/jats:italic>\n                  We demonstrate that while FAD-mutation of either C99 or PSEN1 leads to age-dependent synaptic loss, proteolytically inactive PSEN1 did not. Designed mutations that allow stable E-S complex formation without A\u03b242 or A\u03b2 production likewise result in synaptic degeneration. Moreover, replacement of C99 with variants of a Notch1-based substrate revealed that disrupted processing of another \u03b3-secretase substrate can similarly lead to synaptic degeneration. These results support a model in which synaptic loss can be triggered by toxic, stalled \u03b3-secretase E-S complexes in the absence of A\u03b2 production and not by simple loss of proteolytic function. This new\n                  <jats:italic>C. elegans<\/jats:italic>\n                  system provides a powerful platform to study the role of dysfunctional \u03b3-secretase substrate processing in FAD pathogenesis.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>\n                    Dominantly inherited familial Alzheimer\u2019s disease (FAD) is caused by mutations in the enzyme or substrate that produces amyloid \u03b2-peptides (A\u03b2). These mutations alter enzyme processing of substrate to A\u03b2 and can skew production of A\u03b2 to aggregation-prone forms that deposit as pathological plaques. Nevertheless, whether A\u03b2 is the primary driver of AD remains unresolved. Recent evidence supports a model in which loss of neuronal connections in FAD is due to the stalled enzymatic process of A\u03b2 production, rather than the A\u03b2 products. Using the roundworm\n                    <jats:italic>C. elegans<\/jats:italic>\n                    as a genetic model system, we show here that the stalled process itself, rather than A\u03b2 or reduced enzyme activity, can trigger loss of neuronal connections with age in this simple model animal.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.16.665161","type":"posted-content","created":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T18:55:11Z","timestamp":1753037711000},"source":"Crossref","is-referenced-by-count":1,"title":["A\n                  <i>C. elegans<\/i>\n                  model of familial Alzheimer\u2019s disease shows age-dependent synaptic degeneration independent of amyloid \u03b2-peptide"],"prefix":"10.64898","author":[{"given":"Vaishnavi","family":"Nagarajan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin L.","family":"Libowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1257-2407","authenticated-orcid":false,"given":"Brian D.","family":"Ackley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5721-9092","authenticated-orcid":false,"given":"Michael S.","family":"Wolfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025072303550637000_2025.07.16.665161v1.1","doi-asserted-by":"crossref","first-page":"10692","DOI":"10.1038\/srep10692","article-title":"Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"2025072303550637000_2025.07.16.665161v1.2","first-page":"2","article-title":"Modeling Alzheimer\u2019s Disease in Caenorhabditis elegans","volume":"10","year":"2022","journal-title":"Biomedicines"},{"key":"2025072303550637000_2025.07.16.665161v1.3","doi-asserted-by":"crossref","first-page":"RP102274","DOI":"10.7554\/eLife.102274","article-title":"Alzheimer-mutant \u03b3-secretase complexes stall amyloid \u03b2-peptide production","volume":"13","year":"2025","journal-title":"Elife"},{"key":"2025072303550637000_2025.07.16.665161v1.4","doi-asserted-by":"crossref","first-page":"106961","DOI":"10.1016\/j.nbd.2025.106961","article-title":"Identification of presenilin mutations that have sufficient gamma-secretase proteolytic activity to mediate Notch signaling but disrupt organelle and neuronal health","volume":"212","year":"2025","journal-title":"Neurobiol Dis"},{"key":"2025072303550637000_2025.07.16.665161v1.5","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt59"},{"key":"2025072303550637000_2025.07.16.665161v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/pro.234"},{"key":"2025072303550637000_2025.07.16.665161v1.7","doi-asserted-by":"crossref","unstructured":"Bolduc, D. 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